| 1. |
- Abele, Dace, et al.
(författare)
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Including the liver in the visceral allograft: Impact on donor-specific anti-HLA antibodies and long-term outcomes
- 2024
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Ingår i: HUMAN IMMUNOLOGY. - 0198-8859 .- 1879-1166. ; 85:2
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Tidskriftsartikel (refereegranskat)abstract
- Humoral immunity emerges as a risk factor for graft failure after visceral transplantation (VTx) and development of donor-specific anti-HLA antibodies (DSAs) has been linked with poor outcomes. In most cases, a simultaneous liver transplant can be safely performed in sensitized patients with DSA and appears protective against lymphocytotoxic antibodies. We investigated the incidence of acute (AR) and chronic rejection (CR) in 32 VTx without any B cell-depleting pre-treatment (6 isolated intestinal transplants (IT) and 26 liver-containing, multivisceral transplants (MVT) and assessed the presence of donor-specific antibodies (DSA) pre- and posttransplantation. Twenty-one patients (65 %) developed AR, 15 (57 %) of the MVT and 6 (100 %) of the IT (p = 0.05). CR occurred in 4 IT (60 %, p < 0.001). At one month, de novo DSA were present in 71 % of VTx (66 % MVT vs 100 % IT, p = 0.09). At the last available follow-up, 69 % of the MVT and 50 % of the IT patients were DSA-free. De novo DSA seemed more persistent (7/19, 37 %) than pre-Tx DSA (1/6, 17 %; p = n.s.), de novo DSA were more frequently specific for HLA class II than class I, 16/19 (84 %) vs. 7/19 (37 %; p = 0.003), and HLA-DQ was their most frequent target HLA. DQ mismatches appeared to be a risk factor for developing de novo DSA. In conclusion, liver-containing visceral allografts have superior shortand long-term outcomes compared with liver-free allografts. De novo DSA develop early and frequently after VTx performed without B cell-depleting induction therapy, but the exact role of DSA in the pathogenesis of rejection remains unclear.
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| 2. |
- Borg, Helena, et al.
(författare)
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Four-hour voiding observations detect neurogenic lower urinary tract dysfunction in neonates with anorectal malformation
- 2021
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Ingår i: Journal of Pediatric Urology. - : Elsevier BV. - 1477-5131. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neurogenic lower urinary tract dysfunction (LUTD) has been reported in 20–50% of children with anorectal malformations (ARM). As neurogenic LUTD represents an inherent risk of renal deterioration and urinary tract infections, an early diagnosis is important. The gold standard for evaluating neurogenic LUTD involves invasive urodynamic testing but a useful addition should be an easy-to-perform, non-invasive method of screening. Objective: In this study, we evaluate non-invasive 4 h voiding observations as a screening method for neurogenic LUTD in ARM children. Study design: Thirty-four patients with ARM, excluding those with perineal fistulas, were evaluated using both 4 h voiding observation and urodynamic testing before and after posterior sagittal anorectoplasty (PSARP) at median ages of 0.3 and 1.1 years. In the urodynamic assessment, the gold standard for neurogenic LUTD, nine children received the diagnosis, eight innate and one post-surgery. Results: Five boys with a high urethral fistula and anomalies of the spinal cord had urodynamically diagnosed neurogenic LUTD, a dysfunction also identified in the 4 h voiding observations. The pattern was characterised both by an increase in the number of voiding and the number of interrupted voiding, urinary leakage and elevated residual urine (Figure). In three girls with a vestibular fistula and tethered cord, an urodynamic investigation identified suspected mild neurogenic LUTD. In the voiding observations, an abnormal voiding pattern was not as obvious in the girls as in the five males. One girl with cloaca showed signs of postsurgical denervation damage, which was easily identified in the 4 h voiding observations (high capacity and elevated residual urine). Discussion: In the present study, gender differences in the severity of dysfunction reflected in the free voiding pattern in infants with ARM and neurogenic LUTD is probably the result of the different underlying causes of neurogenic LUTD in boys and girls. Boys with the condition have a congenital malformation of the caudal part of the spinal cord and girls a tethering of the cord. The most obvious limitation of the study was the low number of patients. Despite this, we consider the results worth reporting, since we found that results in the free voiding observations effectively confirmed what was established in the urodynamic investigations. Conclusion: In pre-PSARP patients, 4 h voiding observations can be used to screen for severe neurogenic LUTD requiring attention and treatment. When post-surgical denervation is suspected, the voiding observation is also a good method for indicating the diagnosis.[Formula presented] © 2020 Journal of Pediatric Urology Company
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| 3. |
- Calabrese, Claudia, et al.
(författare)
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Genomic basis for RNA alterations in cancer
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 578:7793, s. 129-136
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Tidskriftsartikel (refereegranskat)abstract
- Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.
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| 4. |
- Daelman, Bo, et al.
(författare)
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Frailty and cognitive function in middle-aged and older adults with congenital heart disease
- 2024
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 83:12, s. 1149-1159
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Tidskriftsartikel (refereegranskat)abstract
- Background: Life expectancy of patients with congenital heart disease (CHD) has increased rapidly, resulting in a growing and aging population. Recent studies have shown that older people with CHD have higher morbidity, health care use, and mortality. To maintain longevity and quality of life, understanding their evolving medical and psychosocial challenges is essential.Objectives: The authors describe the frailty and cognitive profile of middle-aged and older adults with CHD to identify predictor variables and to explore the relationship with hospital admissions and outpatient visits.Methods: Using a cross-sectional, multicentric design, we included 814 patients aged ≥40 years from 11 countries. Frailty phenotype was determined using the Fried method. Cognitive function was assessed by the Montreal Cognitive Assessment.Results: In this sample, 52.3% of patients were assessed as robust, 41.9% as prefrail, and 5.8% as frail; 38.8% had cognitive dysfunction. Multinomial regression showed that frailty was associated with older age, female sex, higher physiologic class, and comorbidities. Counterintuitively, patients with mild heart defects were more likely than those with complex lesions to be prefrail. Patients from middle-income countries displayed more prefrailty than those from higher-income countries. Logistic regression demonstrated that cognitive dysfunction was related to older age, comorbidities, and lower country-level income.Conclusions: Approximately one-half of included patients were (pre-)frail, and more than one-third experienced cognitive impairment. Frailty and cognitive dysfunction were identified in patients with mild CHD, indicating that these concerns extend beyond severe CHD. Assessing frailty and cognition routinely could offer valuable insights into this aging population.
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| 5. |
- Gatzinsky, Cathrine, 1975, et al.
(författare)
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Transabdominal ultrasound of rectal diameter in healthy infants: a prospective cohort study during the first year of life
- 2023
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Ingår i: Journal of Paediatrics and Child Health. - 1034-4810. ; 59:9, s. 1021-1027
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Tidskriftsartikel (refereegranskat)abstract
- AimTransabdominal rectal ultrasound (TRU) is used to measure transverse rectal diameter (TRD) in order to diagnose functional constipation (FC) and megarectum, and to evaluate treatment. The proposed cut-off value is 3.0 cm. Currently, no standardised values exist for children below the age of 4. We used repeated TRUs to establish reference TRD values in healthy infants and to describe rectal diameter in infants with FC. MethodsThis prospective observational cohort study enrolled healthy term babies from a maternity department. TRD measurements were taken at 2 and 12 months of age, and questionnaires completed in interviews helped diagnose FC according to Rome III criteria. ResultsTwo hundred TRUs were performed on 110 infants (62 males). In infants without FC anytime, the mean TRD at 2 months was 1.56 (SD 0.32) cm and at 12 months 1.78 (0.47) cm, while the 95th percentiles were 2.26 and 2.64 cm, respectively. In 77 infants with two TRUs, the mean increase was 0.21 cm (95% confidence interval: 0.099-0.318). Thirteen infants were diagnosed with FC during the study period. At 2 and 12 months of age, there was no difference in TRD between infants with and without FC. ConclusionTRD increased from 2 to 12 months. We suggest 2.3 cm as an upper limit for normal TRD at 2 months and 2.6 cm at 12 months. Infants diagnosed with FC did not have a greater TRD than infants without, either before or after treatment. Further studies are needed to evaluate the usefulness of TRU in infants with FC or megarectum.
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| 6. |
- Hybbinette, Helena, et al.
(författare)
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Longitudinal changes in functional connectivity in speech motor networks in apraxia of speech after stroke
- 2022
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Ingår i: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveThe cerebral substrates of apraxia of speech (AOS) recovery remain unclear. Resting state fMRI post stroke can inform on altered functional connectivity (FC) within cortical language networks. Some initial studies report reduced FC between bilateral premotor cortices in patients with AOS, with lowest FC in patients with the most severe AOS. However, longitudinal FC studies in stroke are lacking. The aims of the present longitudinal study in early post stroke patients with AOS were (i) to compare connectivity strength in AOS patients to that in left hemisphere (LH) lesioned stroke patients without a speech-language impairment, (ii) to investigate the relation between FC and severity of AOS, aphasia and non-verbal oral apraxia (NVOA) and (iii) to investigate longitudinal changes in FC, from the subacute phase to the chronic phase to identify predictors of AOS recovery. MethodsFunctional connectivity measures and comprehensive speech-language assessments were obtained at 4 weeks and 6 months after stroke in nine patients with AOS after a LH stroke and in six LH lesioned stroke patients without speech-language impairment. Functional connectivity was investigated in a network for speech production: inferior frontal gyrus (IFG), anterior insula (aINS), and ventral premotor cortex (vPMC), all bilaterally to investigate signs of adaptive or maladaptive changes in both hemispheres. ResultsInterhemispheric vPMC connectivity was significantly reduced in patients with AOS compared to LH lesioned patients without speech-language impairment. At 6 months, the AOS severity was associated with interhemispheric aINS and vPMC connectivity. Longitudinal changes in FC were found in individuals, whereas no significant longitudinal change in FC was found at the group level. Degree of longitudinal AOS recovery was strongly associated with interhemispheric IFG connectivity strength at 4 weeks. ConclusionEarly interhemispheric IFG connectivity may be a strong predictor of AOS recovery. The results support the importance of interhemispheric vPMC connection in speech motor planning and severity of AOS and suggest that also bilateral aINS connectivity may have an impact on AOS severity. These findings need to be validated in larger cohorts.
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| 7. |
- Larsson, Cornelia, et al.
(författare)
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Facial affect recognition in first-episode psychosis is impaired but not associated with psychotic symptoms.
- 2022
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Ingår i: Heliyon. - : Elsevier. - 2405-8440. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Social dysfunction is a key feature of psychotic disorders such as schizophrenia linked to disability. Less is known about social functioning in the early stages of the disorder and if there is an association to psychotic symptoms.Aims: Investigate if antipsychotic drug-naïve or briefly medicated individuals with first-episode psychosis (FEP), have impaired facial affect recognition (FAR) compared to control participants and if psychotic symptoms are associated with the FAR ability.Method: Individuals with FEP (n = 67) and control participants (n = 51) performed a computer-aided FAR task on basic emotions. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Group performances were compared using age and gender as covariates. The associations between FAR and performance on the subscales of PANSS were analyzed.Results: Compared to control participants, individuals with FEP were impaired in general FAR (Beta = -2.04 [95 % conf: -3.75/-1.62], p < 0.001) and FAR of negative emotions (Beta = -1.74 [95 % conf: -3.08/-1.22], p < 0.001), driven by difficulties in recognition of anger and disgust. In both groups, there was a pattern of mistaking negative emotions for other negative emotions. There were no significant group differences in FAR of happiness. No significant associations between FAR and psychotic symptoms were observed.Discussion: The results indicate that FAR, an underlying mechanism of social functioning is impaired early in the course of psychotic disorders. Current findings do not support the hypothesis that misinterpretation of facial expressions in individuals with FEP underlies or contributes to symptoms of psychosis.
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| 8. |
- Lee, Maria, et al.
(författare)
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Cognitive Function and Variability in Antipsychotic Drug-Naive Patients With First-Episode Psychosis : A Systematic Review and Meta-Analysis.
- 2024
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Ingår i: JAMA psychiatry. - 2168-6238.
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Cognitive impairment contributes significantly to clinical outcome and level of function in individuals with psychotic disorders. These impairments are present already at psychosis onset at a group level; however, the question of heterogeneity in cognitive function among patients has not been systematically investigated.OBJECTIVE: To provide an updated quantification of cognitive impairment at psychosis onset before patients receive potentially confounding antipsychotic treatment, and to investigate variability in cognitive function compared with healthy controls.DATA SOURCES: In this systematic review and meta-analysis, PubMed articles were searched up to September 15, 2022.STUDY SELECTION: Original studies reporting data on cognitive function in antipsychotic drug-naive patients with first-episode psychosis (FEP) were included.DATA EXTRACTION AND SYNTHESIS: Data were independently extracted by 2 researchers. Cognitive tasks were clustered according to 6 domains of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the domain of executive function. Random-effects model meta-analyses of mean differences and coefficient of variation ratios (CVRs) were performed, as well as meta-regressions, assessment of study quality, and publication bias.MAIN OUTCOMES AND MEASURES: The main outcome measure was Hedges g for mean differences in cognition and CVR for within-group variability.RESULTS: Fifty studies were included in the analysis with a total of 2625 individuals with FEP (mean [SD] age, 25.2 [3.6] years, 60% male; 40% female) and 2917 healthy controls (mean [SD] age, 26.0 [4.6]; 55% male; 45% female). In all cognitive domains, the FEP group displayed significant impairment compared with controls (speed of processing: Hedges g = -1.16; 95% CI, -1.35 to -0.98; verbal learning: Hedges g = -1.08; 95% CI, -1.28 to -0.88; visual learning: Hedges g = -1.05; 95% CI, -1.27 to -0.82; working memory: Hedges g = -1.04; 95% CI, -1.35 to -0.73; attention: Hedges g = -1.03; 95% CI, -1.24 to -0.82; reasoning/problem solving: Hedges g = -0.90; 95% CI, -1.12 to -0.68; executive function: Hedges g = -0.88; 95% CI, -1.07 to -0.69). Individuals with FEP also exhibited a larger variability across all domains (CVR range, 1.34-1.92).CONCLUSIONS AND RELEVANCE: Results of this systematic review and meta-analysis identified cognitive impairment in FEP before the initiation of antipsychotic treatment, with large effect sizes. The high variability within the FEP group suggests the need to identify those individuals with more severe cognitive problems who risk worse outcomes and could benefit the most from cognitive remediation.
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| 9. |
- Martinez, Maria Månsson, et al.
(författare)
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Beta cell function in participants with single or multiple islet autoantibodies at baseline in the TEDDY Family Prevention Study : TEFA
- 2021
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Ingår i: Endocrinology, Diabetes & Metabolism. - : Wiley. - 2398-9238. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim of the present study was to assess beta cell function based on an oral glucose tolerance test (OGTT) in participants with single islet autoantibody or an intravenous glucose tolerance test (IvGTT) in participants with multiple islet autoantibodies. Materials and methods: Healthy participants in Sweden and Finland, between 2 and 49.99 years of age previously identified as positive for a single (n = 30) autoantibody to either insulin, glutamic acid decarboxylase, islet antigen-2, zinc transporter 8 or islet cell antibodies or multiple autoantibodies (n = 46), were included. Participants positive for a single autoantibody underwent a 6-point OGTT while participants positive for multiple autoantibodies underwent an IvGTT. Glucose, insulin and C-peptide were measured from OGTT and IvGTT samples. Results: All participants positive for a single autoantibody had a normal glucose tolerance test with 120 minutes glucose below 7.70 mmol/L and HbA1c values within the normal range (<42 mmol/mol). Insulin responses to the glucose challenge on OGTT ranged between 13.0 and 143 mIU/L after 120 minutes with C-peptide values between 0.74 and 4.60 nmol/L. In Swedish participants, the first-phase insulin response (FPIR) on IvGTT was lower in those positive for three or more autoantibodies (n = 13; median 83.0 mIU/L; range 20.0-343) compared to those with two autoantibodies (n = 15; median 146 mIU/L; range 19.0-545; P =.0330). Conclusion: Participants positive for a single autoantibody appeared to have a normal beta cell function. Participants positive for three or more autoantibodies had a lower FPIR as compared to participants with two autoantibodies, supporting the view that their beta cell function had deteriorated.
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| 10. |
- Martinez, Maria Månsson, et al.
(författare)
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Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA
- 2022
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Ingår i: Clinical diabetes and endocrinology. - : Springer Science and Business Media LLC. - 2055-8260. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.METHODS: Subjects (n = 57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24).RESULTS: Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was - 1.88 (- 2.71, - 1.05) p = 3.49 × 10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (- 0.80 (- 1.58, - 0.02), p = 0.046).CONCLUSIONS: The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02605148 , November 16, 2015.
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